The present invention relates to chemical compounds useful in the treatment of disorders of the central nervous system (CNS), such as anxiety and all forms of epilepsy, particularly in humans. The invention also relates to the use of such compounds, pharmaceutical preparations containing such compounds and to methods of preparing such compounds.
Anxiety disorders affect an estimated 73 million people world-wide. The benzodiazepines have provided the dominant therapy for anxiety over the past three decades and there is no doubt that they are remarkably effective anxiolytics. However, chronic administration of benzodiazepines produces severe dependence liability, withdrawal syndromes, and side effects (sedation, amnesia, muscle relaxation). The only non-benzodiazepine anxiolytic that has been launched over the past decade is the 5-HT receptor ligand buspirone (Buspar(copyright)). This drug has had a remarkable commercial success despite being regarded as a weak anxiolytic (compared with the benzodiazepines) and having a long latency to onset of therapeutic action (2-4 weeks). In addition, buspirone and all related 5-HT1A partial agonists suffer from a dose-limiting side-effect profile comprising nausea, vertigo and endocrine changes.
The aetiology of anxiety disorders is not fully understood, but it is now established that benzodiazepines act by potentiating GABAergic neurotransmission although there is strong evidence that other neurotransmitter systems are modulated indirectlyxe2x80x94in particular, the serotonergic and noradrenergic systems. Many pharmaceutical companies have invested considerable resource into the development of serotonergic anxiolytics. However, it is now apparent that ligands selective for 5-HT receptor subtypes, despite displaying anxiolytic-like activity in a restricted range of anxiety models, have, at best, very weak and/or non-dose-related anxiolytic effects in the clinic. The 5-HT3 receptor antagonists are now discredited as psychotropics: they have a restricted range of activity in functional and anxiety models; they show no convincing anxiolytic effects in the clinic; and they are now accepted only as useful anti-emetics. The 5-HT2A antagonists similarly are regarded as ineffective in terms of psychotropic activity. The clinical utility of 5-HT1A receptor agonists and partial agonists is severely limited by their intrinsically weak action and by the dose-limiting side-effects (vertigo, endocrine changes, nausea) which become more intense as the agonist efficacy of these molecules is increased. The selective CCKB receptor antagonists have displayed an unimpressive preclinical profile similar to that of selective 5-HT ligands such as the 5-HT3 antagonists.
Serotonergic anxiolytics include the selective serotonin reuptake inhibitors (SSRI""s) which, in addition to displaying antidepressant properties, are also effective in anxiety disorders such as panic disorder and obsessive-compulsive disorder. However, as with their antidepressant action, the major drawback with these compounds is the long delay (6-8 weeks) in the onset of clinical improvement following chronic administration.
A strategy in recent years towards improving the clinical profile of classical benzodiazepines is that of developing benzodiazepine receptor partial agonists, according to the rationale that they would have a more selective anxiolytic action and be less liable to induce dependence. However, this approach appears to have failed owing to the very weak anxiolytic actions of these compounds and their poor side-effect profiles (there is either a low or non-existent ratio between anxiolytic and sedative doses).
U.S. Pat. No. 4,956,359 and EP-A-0194112 disclose 3-aryloxy and 3-arylthio azetidinecarboxamides and their anti-convulsant and anti-epileptic activity. However, these compounds, like the benzodiazepines, have low water solubility which leads to difficulties in formulation.
There remains therefore a need for novel anxiolytic and anti-epileptic agents which do not suffer the above-mentioned drawbacks.
According to the present invention there is provided a chemical compound of formula (1) 
wherein:
R1 is aryl; and
R2, R3, R4, R5 and R6 which may be the same or different are selected from H, alkyl and aryl;
and pharmaceutically acceptable addition compounds thereof.
Reference in the present specification to an xe2x80x9calkylxe2x80x9d group means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl (including allyl) or alkynyl (including propargyl)) hydrocarbyl radical. Where cyclic or acyclic the alkyl group is preferably C1 to C12, more preferably C1 to C8 (such as methyl, ethyl, propyl, isopropyl butyl, isobutyl, tert-butyl, amyl, isoamyl, hexyl, heptyl, octyl).
Reference in the present specification to an xe2x80x9carylxe2x80x9d group means a mono or bicyclic aromatic group, such as phenyl or naphthyl.
The alkyl and aryl groups may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 or 2 substituents. Substituents may include:
Preferred substituents include alkyl, aryl, halo, or an halogen-containing group such as trifluoromethyl.
As used herein, the term xe2x80x9calkoxyxe2x80x9d means alkyl-Oxe2x80x94 and xe2x80x9calkoylxe2x80x9d means alkyl-COxe2x80x94.
As used herein, the term xe2x80x9chalogenxe2x80x9d means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine or chlorine radical.
The compounds of formula (1) may exist in a number of diastereomeric and/or enantiomeric forms. Reference in the present specification to xe2x80x9ca compound of formula (1)xe2x80x9d is a reference to all stereoisomeric forms of the compound and includes a reference to the unseparated stereoisomers in a mixture, racemic or non-racemic, and to each stereoisomer in its pure form.
In the compounds of formula (1), preferably R1 is a substituted or unsubstituted aryl group selected from phenyl, naphthyl and indanyl, more preferably R1 is a substituted phenyl, naphthyl or indanyl, more preferably R1 is a phenyl, naphthyl or indanyl having 1 to 3 substituents and, more preferably, R1 is a phenyl, naphthyl or indanyl having 1 or 2 substituents. It is preferred that R1 is a mono- or di-substituted phenyl or naphthyl, preferably a mono- or di-substituted phenyl, and most preferably a mono-substituted phenyl.
Where R1 is a phenyl having 1 substituent, the phenyl group is preferably meta- or para-substituted. Where R1 is a phenyl having 2 substituents, the phenyl group is preferably a 3,4-disubstituted phenyl or a 3,5-disubstituted phenyl, more preferably a 3,4-disubstituted phenyl.
Where R1 is a naphthyl group it is preferred that R1 is a 2-naphthyl group. Where R1 is an indanyl group, it is preferred that R1 is a 5-indanyl group.
Where R1 is substituted, the preferred substituents are selected from chloro, fluoro, bromo, iodo, trifluoromethyl, tertiary-butyl, phenyl, CO2Me and CN, preferably from chloro, fluoro, trifluoromethyl and tertiary-butyl, and more preferably from chloro, trifluoromethyl and tertiary-butyl.
Where R1 is di-substituted, it is preferred that each substituent is independently selected from halo, preferably chloro and fluoro. Where R1 is di-substituted, it is preferred that R1 is substituted by two chloro groups or by one chloro and one fluoro group, and more preferably by two chloro groups.
The most preferred R1 groups are selected from 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-tert-butylphenyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3,4-dichlorophenyl and 3,5-dichlorophenyl.
In the compounds of formula (1), R2 is selected from H, alkyl (including hydroxyalkyl such as CH2OH) and aryl. Preferably R2 is selected from H and alkyl. Where R2 is alkyl, R2 is preferably methyl. Where R2 is aryl, R2 is preferably phenyl. Preferably R2 is H or methyl. More preferably R2 is methyl.
In the compounds of formula (1), R3 is selected from H, alkyl (including hydroxyalkyl such as CH2OH) and aryl. Preferably R3 is selected from H and alkyl. Where R3 is alkyl, R3 is preferably methyl. Where R3 is aryl, R3 is preferably phenyl. Preferably R3 is H or methyl.
In the compounds of formula (1), preferably R4 is selected from H and alkyl (including hydroxyalkyl). Preferably R4 is H or methyl. More preferably R4 is H.
In the compounds of formula (1), preferably R5 is selected from H and alkyl (including carboxy, alkoxycarbonyl and aminocarbonyl). R5 is preferably H or methyl. More preferably R5 is H.
In the compounds of formula (1), preferably R6 is selected from H and alkyl (including carboxy, alkoxycarbonyl and aminocarbonyl). R6 is preferably H or methyl. More preferably R6 is H.
In one embodiment of the invention R2, R3, R4, R5 and R6 are independently selected from H and alkyl.
In a further embodiment of the invention, R2 is H and R3 is methyl or R2 is methyl and R3 is H.
In a further embodiment of the invention R4, R5 and R6 are H.
In the compounds of formula (1), R2 and R4 may optionally be linked by a saturated divalent radical chain of carbon atoms to form a 5, 6 or 7 membered ring, preferably a 5 membered ring, such as tetrahydrofuran.
In the compounds of formula (1), R2 and R3 may optionally be linked by a saturated divalent radical chain of carbon atoms to form a 5, 6 or 7 membered ring, preferably a 6 membered ring, such as cyclohexane.
In the compounds of formula (1), R2 and R5 may optionally be linked by a saturated divalent radical chain of carbon atoms to form a 5, 6 or 7 membered ring, preferably a 6 membered ring, such as cyclohexane.
Particularly preferred compounds are as follows:
Of these, the preferred compounds are: (R)-3-(4tert-butylphenoxy)-N-(2-hydroxypropyl)azetidine-1-carboxamide, (R)-3-(4-chlorophenoxy)-N-(2-hydroxypropyl)azetidine-1-carboxamide, (S)-3-(4-chlorophenoxy)-N-(2-hydroxypropyl)azetidine-1-carboxamide, (R)-3-(3,4-dichlorophenoxy)-N-(2-hydroxypropyl)azetidine-1-carboxamide, (R)-3-(4-trifluoromethyl)phenoxy-N-(2-hydroxypropyl)azetidine-1-carboxamide and (R)-3-(3-trifluoromethyl)phenoxy-N-(2-hydroxypropyl)azetidine-1-carboxamide.
The compounds of the present invention, particularly those compounds in which R4 is hydrogen, are more water soluble than the compounds previously used as anxiolytic or anti-epileptic agents. A further advantage of the compounds of the present invention is the presence of a hydroxyl group which provides an available functionality for subsequent derivatisation for the further modification of physical and chemical properties.
According to a further aspect of the present invention there is provided a compound according to the present invention for use in therapy.
The compounds of the present invention may be used in the treatment (including prophylaxis) of CNS disorders. In particular, the compounds of the present invention may be used in the treatment (including prophylaxis) of anxiety, epilepsy, insomnia, including travel insomnia and insomnia associated with terminal illness, alcohol withdrawal syndrome, chronic and acute pain, neurodegenerative diseases (for example, senile dementia) and symptoms related to withdrawal from substance abuse. The compounds may also be used in the relief of spasticity. The compounds of the present invention may also be used in muscle relaxation prior to surgery or surgical manipulation or as pre-medication prior to surgery..
In a preferred embodiment of the present invention, the compounds are used in the treatment (including prophylaxis) of anxiety or epilepsy.
Anxiety includes generalised anxiety disorder (GAD), panic disorder, panic disorder plus agoraphobia, simple (specific) phobias (e.g. arachnophobia, performance anxiety such as public speaking), social phobias, post-traumatic stress disorder, anxiety associated with depression, and obsessive compulsive disorder (OCD).
Epilepsy is a chronic disorder characterised by recurrent seizures. Two forms of epilepsy existxe2x80x94partial and generalised epilepsyxe2x80x94and each type is subdivided into idiopathic (cause unknown) or symptomatic (cause known). There are two fundamental types of seizures: partial seizures which includes simple partial seizures, complex partial seizures, and partial seizures secondarily generalised; and generalised seizures which includes generalised tonic-clonic seizures (grand mal), absence seizures (petit mal), myoclonic seizures, atonic seizures, clonic seizures, and tonic seizures.
According to a further aspect of the present invention there is provided use of a compound of the present invention in the manufacture of a medicament for the treatment (including prophylaxis) of CNS disorders, preferably anxiety, epilepsy, insomnia, including travel insomnia and insomnia associated with terminal illness, alcohol withdrawal syndrome, chronic and acute pain, neurodegenerative diseases, symptoms relating to withdrawal from substance abuse or spasticity, and more preferably anxiety or epilepsy.
According to a further aspect of the present invention there is provided use of a compound of the present invention in the manufacture of a medicament for muscle relaxation prior to surgery or surgical manipulation or as pre-medication prior to surgery.
The invention further provides a method of treatment (including prophylaxis) of CNS disorders, preferably anxiety, epilepsy, insomnia, including travel insomnia and insomnia associated with terminal illness, alcohol withdrawal syndrome, chronic and acute pain, neurodegenerative diseases, symptoms relating to withdrawal from substance abuse and spasticity, and more preferably anxiety or epilepsy, comprising administering to a patient in need of such treatment an effective dose of a compound according to the present invention.
The invention further provides a method of muscle relaxation prior to surgery or surgical manipulation or as pre-medication prior to surgery, comprising administering to a patient in need thereof an effective dose of a compound according to the present invention.
According to a further aspect of the present invention there is provided a method of preparing a compound of the present invention.
Compounds of the invention may be prepared according to the reaction scheme (where P is a nitrogen protecting group). R1, R2, R3, R4, R5, R6 are as previously defined. The 3-(aryloxy)azetidine (III) may be formed by reaction of the azetidinol (II) either with an arylalkanol (R1OH) and diethylazo dicarboxylate and triphenyl phosphine or with a substituted aryl fluoride (R1F) and a strong base such as sodium hydride. Formation of the azetidine (IV) is achieved by reaction of (III) with a suitable nitrogen deprotection agent. For example, if P is a diphenylmethyl group, then deprotection may be carried out by treatment with 1-chloroethyl chloroformate followed by methanol. The urea (I) is formed by reaction of azetidine (IV) with an N-alkylisocyanate or an N-alkylcarbamoyl chloride and a base such as triethylamine or potassium carbonate. Alternatively, the urea may be prepared directly from the azetidine (III) without isolation of an intermediate such as the secondary amine (IV). For example, when P is a diphenylmethyl group, azetidine (III) may be treated with phosgene followed by alkylamine R4O.CR2R3.CR5R6.NH2 to give urea (I) directly. 
The invention further provides a pharmaceutical composition comprising a compound according to the present invention in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound according to the present invention with a pharmaceutically acceptable carrier or excipient.
Compounds of the present invention may be administered in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use including transmucosal and transdermal use, for example a cream, ointment, gel, aqueous or oil solution or suspension, salve, patch or plaster, for nasal use, for a example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oil solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients, using standard techniques well known to those skilled in the art of pharmacy. Preferably, the compound is administered orally.
For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.
Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer""s solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
It will be appreciated that the dosage levels used may vary over quite a wide range depending upon the compound used, the severity of the symptoms exhibited by the patient and the patient""s body weight.